[Efficacy of Hyper-CVAD/MA and CHALL-01 regimens in the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia patients under 60 years old].

Objective: To compare the difference of efficacy between traditional Hyper-CVAD/MA regimen and the adolescents inspired chemotherapy regimen, CH ALL-01, in treatment of adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) . Methods: In this study we retrospectively analyzed 158 Ph(+) ALL patients receiving Hyper-CVAD/MA regimen (n=63) or CHALL-01 regimen (n=95) in our center and Changzheng hospital from January 2007 to December 2017, excluding patients with chronic myeloid leukemia in blast crisis. Tyrosine kinase inhibitor (TKI) was administered during induction and consolidation chemotherapy. Patients who underwent hematopoietic stem cell transplantation received TKI as maintenance therapy. Results: Of them, 91.1% (144/158) patients achieved complete remission (CR) after 1-2 courses of induction. CR rate was 90.5% (57/63) for patients in Hyper-CVAD/MA group and 91.6% (87/95) for patients in CHALL-01 group. There was no difference in CR rates between the two groups (χ(2)=0.057, P=0.811) . The last follow-up was June 2018. A cohort of 134 CR patients could be used for further analysis, among them, 53 patients received Hyper-CVAD/MA regimen and other 81 patients received CHALL-01 regimen. The molecular remission rates were significantly higher in CHALL-01 group (complete molecular response: 44.4%vs 22.6%; major molecular response: 9.9% vs 18.9%) (χ(2)=7.216, P=0.027) . For the patients in Hyper-CVAD/MA group, the 4-year overall survival (OS) was 44.81% (95%CI: 30.80%-57.86%) and the 4-year disease free survival (DFS) was 37.95% (95%CI: 24.87%-50.93%) . For patients received CHALL-01 regimen, the 4-year OS was 55.63% (95%CI: 39.07%-69.36%) (P=0.037) and 4 year DFS was 49.06% (95%CI: 34.24%-62.29%) (P=0.015) , while there was no significant difference in 4 year cumulative incidence of relapse (CIR) (P=0.328) or cumulative incidence of nonrelapse mortality (CI-NRM) (P=0.138) . The rate of pulmonary infection was lower in patients received CHALL-01 regimen compared with patients received Hyper-CVAD regimen (43.4% vs 67.9%, χ(2)=7.908, P=0.005) . Conclusions: Outcome with CHALL-01 regimen appeared better than that with the Hyper-CVAD/MA regimen in Ph(+) ALL, which has lower incidence of pulmonary infection, higher molecular remission rate and better OS and DFS.

Factors influencing QTL mapping accuracy under complicated genetic models by computer simulation.

The accuracy of quantitative trait loci (QTLs) identified using different sample sizes and marker densities was evaluated in different genetic models. Model I assumed one additive QTL; Model II assumed three additive QTLs plus one pair of epistatic QTLs; and Model III assumed two additive QTLs with opposite genetic effects plus two pairs of epistatic QTLs. Recombinant inbred lines (RILs) (50-1500 samples) were simulated according to the Models to study the influence of different sample sizes under different genetic models on QTL mapping accuracy. RILs with 10-100 target chromosome markers were simulated according to Models I and II to evaluate the influence of marker density on QTL mapping accuracy. Different marker densities did not significantly influence accurate estimation of genetic effects with simple additive models, but influenced QTL mapping accuracy in the additive and epistatic models. The optimum marker density was approximately 20 markers when the recombination fraction between two adjacent markers was 0.056 in the additive and epistatic models. A sample size of 150 was sufficient for detecting simple additive QTLs. Thus, a sample size of approximately 450 is needed to detect QTLs with additive and epistatic models. Sample size must be approximately 750 to detect QTLs with additive, epistatic, and combined effects between QTLs. The sample size should be increased to >750 if the genetic models of the data set become more complicated than Model III. Our results provide a theoretical basis for marker-assisted selection breeding and molecular design breeding.

Serum 25-hydroxyvitamin D levels and peripheral neuropathy in patients with type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Vitamin D is a multifunctional pro-hormone and has widespread actions in human body. Several studies showed a possible association between vitamin D deficiency and diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes, but no definite conclusion was available. METHODS: A systematic review and meta-analysis was performed to comprehensively assess the association between serum 25-hydroxyvitamin D [25(OH)D] levels and DPN in patients with type 2 diabetes. Data from eligible studies were pooled using meta-analysis. RESULTS: Six studies that involved a total of 1,484 type 2 diabetic patients were finally included into the meta-analysis. Meta-analysis showed that there were obviously decreased serum 25(OH)D levels in DPN patients [weighted mean difference (WMD) = -6.36 ng/ml, 95 % confidence interval (95 % CI) -8.57 to -4.14, P < 0.00001]. Vitamin D deficiency was also significantly associated with increased risk of DPN in patients with type 2 diabetes [odds ratio (OR) 2.88, 95 % CI 1.84-4.50, P < 0.00001]. Meta-analysis of three studies with adjusted estimates showed that vitamin D deficiency was independently associated with increased risk of DPN in patients with type 2 diabetes (OR 2.68, 95 % CI 1.67-4.30, P < 0.0001). Sensitivity analysis showed that there was no obvious change in the pooled estimates. CONCLUSION: Vitamin D is involved in the development of DPN in type 2 diabetic patients, and vitamin D deficiency is very likely to be associated with DPN in type 2 diabetic patients. Further studies are needed to validate the association between vitamin D deficiency and DPN.

Expression of Smac induced by the Egr1 promoter enhances the radiosensitivity of breast cancer cells.

Breast cancer is one of the most prevalent cancers worldwide. Moreover, despite advances in antineoplastic therapies, induction of tumor cell death without off-target cytotoxicity remains a challenge. However, recent developments in localized radiotherapy and gene therapy have provided an opportunity to explore the potential for these strategies to be additive for the induction of cell death in tumor cells. Here, a novel adenoviral shuttle vector containing the proapoptotic gene Smac under the control of the ionizing radiation (IR)-induced Egr1 promoter was constructed. Following the transient transfection of the construct into MCF-7 and MDA-MB-435 breast cancer cell lines, acute and abundant expression of Smac was observed in response to IR treatment. Further analysis confirmed that the induction of Smac expression resulted in a decrease in cell viability, a slower rate of cell growth, a higher level of apoptosis and altered cell cycle progression. Using a clonogenic assay, IR-induced Smac expression was also found to significantly sensitize Smac-expressing cells to radiation-induced cell death. Taken together, these data suggest that Smac expression driven by the Egr1 promoter has the potential to serve as a radiotherapy-dependent gene therapy agent.

Radiosensitization of breast cancer cells by TRAIL-endostatin-targeting gene therapy.

One of the key issues in cancer radiotherapy research is to sensitize tumor cells to the cell killing effects of ionizing radiation while leaving normal tissues intact. One potential approach to achieve this is gene-radiotherapy, i.e. a combination of radiation therapy and gene therapy. It is to choose certain exogenous radiation-inducible regulatory genes, for example, early growth response-1 (Egr-1), and transcript its downstream tumor-therapeutic genes under ionizing radiation so as to kill the tumor cells synergistically by the expressed gene products together after transfection and irradiation exposure. In this study, we engineered a plasmid encoding both TRAIL and endostatin under the control of the radiation-inducible Egr-1 promoter, and evaluated its anti-tumor efficacy in combination with radiotherapy. Our plasmid showed significant efficacy in up-regulating the levels of TRAIL and endostatin proteins after transfected into breast cancer cells and exposed to X-ray irradiation. The detected cellular effects in vitro manifested that TRAIL-endostatin-based gene therapy could enhance radiosensitizing effects in breast cancer cells in terms of tumor cell growth inhibition, promoting apoptosis and the induction of cell cycle arrest. In summary, our results suggest that TRAIL-endostain-targeting approach might be a promising method to sensitize solid tumors to radiation therapy.

Trends of heavy metal components in the Arctic aerosols and their relationship to the emissions in the Northern Hemisphere.

Twenty-one years of observations (1980-2000) of weekly mean concentrations of major anthropogenic and natural metals in the aerosol of the lower Arctic troposphere at Alert have been analyzed by time series analysis for seasonal and long-term trends and by positive matrix factorization for major aerosol components with which metals are associated. Metals at Alert exhibit distinct seasonal variations depending on the source and origin of the metals. Anthropogenic metals such as Pb, Zn and Cu and the sea-salt components Na and Mg exhibit maxima in winter and minima in summer. Similar variations were observed for non-soil fractions of V and Mn. Weak seasonal variations were found for soil-related metals such as Al, Ba, Ca and Fe. If any trend is evident in anthropogenic metals, it is a slight decrease from 1980 to mid-1990s but generally the variation is not monotonic. It is found through the winter observations of Pb, Zn, Ni and Cu concentrations that the decline trends have been leveled off and started to increase again around 1995. No long-term trends were detected in Na, Mg and Ca concentrations but a slight decrease is observed for soil components Al, Fe and Ti after 1995. Analysis showed that these trends are mostly associated with the anthropogenic emission variations surrounding the Arctic regions.

Effects of low dose radiation on signal transduction of neurons in mouse hypothalamus.

OBJECTIVE: Effects of low dose radiation on signal transduction of neurons in mouse hypothalamus were investigated. METHODS: In the present study competitive protein binding assay, radioimmunoassay, in situ hybridization and immunohistochemistry were used to observe the effects of whole-body irradiation with 75 mGy X-rays on the contents of cAMP and cGMP and the expressions of c-fos mRNA, Fos protein and proopiomelanocortin (POMC) mRNA in the neurons of mouse hypothalamus. RESULTS: The results showed that cAMP content in mouse hypothalamus immediately increased significantly and reached the peak value in 15 min after irradiation, and then returned to near sham-irradiation level 1 h after irradiation, followed by a small fluctuation of increase and decrease; the changes of cGMP content were basically opposite to those of cAMP content, while the changes of cAMP/cGMP ratio were basically consistent with those of cAMP content. The expression of c-fos mRNA in the neurons of hypothalamus appeared 15 min after irradiation, reached its peak value within 1 h, began to abate 2 h with its total disappearance 8 h after irradiation; the expression of Fos protein reached its peak value 8 h after irradiation, and then gradually returned to sham-irradiation level 48 h after irradiation; the expression of POMC mRNA decreased significantly 1 h after irradiation and remained at a lower level in the observation period of 12 h. CONCLUSION: These findings implicate that low dose radiation may potentiate the activity of the neurons in mouse hypothalamus, expedite their signal transduction, and down-regulate the functions of hypothalamus-pituitary-adrenocortical axis.

Adaptive response of thymocyte apoptosis and cell cycle progression induced by low dose X-ray irradiation in mice.

The dose-effect of adaptive response of thymocyte apoptosis and cell cycle progression induced by whole-body X-ray irradiation (WBI) was studied in male Kunming mice. The inductive doses (D1) were 25, 50, 75, 100 or 200 mGy 6 h before the challenging doses (D2) of 1.0, 1.5 or 2.0 Gy. The changes in the percentages of the thymocyte apoptotic bodies (TAB) and the cells in different phases of cell cycle were measured with flow cytometry. The percentages of TAB decreased, the arrests of G1 and G2 + M phases diminished, and the cells of DNA synthesis of S phase increased when the D1 + D2 groups was compared with the D2 groups. When D1 was 200 mGy, the adaptive response of thymocyte apoptosis and cell cycle progression were no longer induced by low dose radiation (LDR). In addition, the extracellular fluid from the splenocytes were cultured with Con A for 48 h in vitro 24 h after 75 mGy WBI was placed in the murine thymocyte suspension from mice irradiated with 2.0 Gy WBI and co-incubated. The thymocyte apoptosis decreased. Especially, noteworthy was that the percentages of TAB after the incubation for 72 h were significantly lower than those in 2.0 Gy irradiated thymocytes (P < 0.05). These results indicate that when the mice were irradiated with 25-100 mGy (D1, 12.5 mGy/min) 6 h before 1.0-2.0 Gy (D2, 0.287 Gy/min) exposure, an adaptive response of thymocyte apoptosis and cell cycle progression may be induced under the condition of WBI, and LDR (75 mGy) may change the microenvironment of immune cells and decrease the thymocyte apoptosis.

A nuclear mass spectrometer for studying radon progeny clusters.

A Nuclear Mass Spectrometer (NMS) system was developed and used to investigate the cluster formation of radon progeny (218Po) in gaseous H2O and H2O-SO2 environments. This NMS combines the mass-separation ability of a mass spectrometer and the low detection limit of a surface barrier detector for alpha particles and enables the detection of individual radon progeny cluster ions of defined mass at the molecular level. Clusters in the form of 218Po+(H2O)n were experimentally observed for 218Po at a relative humidity of 0.1%. The number n ranged from 1 to 7 with 4 being the most abundant peak under these conditions. No charged cluster of 218Po was detected when the relative humidity was 90%, possibly due to a neutralization process. On addition of SO2 at a low relative humidity, 218Po+(H2O)n (H2SO4)m clusters were experimentally detected for the first time by the NMS system in this study with n from 0-4 and m from 0-3. The maximum distribution occurs at a radius of about 3.65 angstrom or a mobility of about 2.00 cm2 V-1 s-1. These maximum clusters correspond to a composition of 218Po+(H2SO4)2 or 218Po+(H20)2 (H2SO4)1.

Harmful effects of MSG on function of hypothalamus-pituitary-target gland system.

It has been demonstrated that neonatal administration of monosodium glutamate (MSG) results in a clearly defined lesion of the arcuate nucleus (AN) of the hypothalamus. The present study shows that fat was accumulated in the abdomen of male rats treated with MSG; weights of the body, pituitary and testis were lower; beta-EP content in hypothalamus decreased while L.EnK content increased; serum LH, FSH, TSH, GH and TS levels all decreased in varying degrees while serum PRL level significantly increased. The cAMP content lowered in pituitary, but nor in testes; clear histological changes occurred in testicular tissue; Se-GSH-Px activity in both testis and adrenal gland lowered while LPO level significantly increased. Both Se-GSH-Px activity and LPO level in liver increased. These results indicate that MSG is harmful to the function of the hypothalamus-pituitary-target system of neonatal rats.

[Protective effect of panaxatriols on function of reproductive endocrine axis in radiation-injured rats].

After whole body irradiation with X-ray 5 Gy (radiation condition: 0.31 Gy.min-1, 200 kV, 10 mA, 0.5 mm Cu and 1.0 mm Al), the male rats were given ip panaxatriols 5 mg.d-1 24 h before and after irradiation for 14 d. The results showed that hypothalamic leu-enkephalin (165 +/- 12 vs 131 +/- 14 pg.mg-1), pituitary beta-endorphin (2.3 +/- 0.5 vs 1.6 +/- 0.3 ng.mg-1) contents, and serum testosterone (1.66 +/- 0.15 vs 0.82 +/- 0.23 ng.ml-1) level were decreased, while serum FSH (1.34 +/- 0.10 vs 1.99 +/- 0.10 ng.ml-1) level increased in irradiation group vs normal control. These indices approached to control levels in irradiation + panaxatriols group. These suggest that panaxatriols have protective effects on reproductive endocrine axis and promote their recovering course from the radiation injuries.

Concentrations of homovanillic Acid and gonadal hormones in the serum of male schizophrenic patients.

The concentrations of serum homovanillic acid (HVA), luteinizing liormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) were examined in 20 male schizophrenic patients not taking neuroleptic drugs, 44 treated with neuroleptic drugs, and 15 male healthy control subjects. Kurskal-Wallis analysis of variance showed no significant difference among the three groups in serum HVA, FSH, LH or testosterone although high concentrations were found in tlte patients not taking neuroleptic drugs. There was a significant positive correlation between serum HVA and FSH in the patients not taking neuroleptics. The present results suggest that the change of gonadal hormones may be related to the pathogenesis of schizophrenia.